Computational chemist Marti Head was among many scientists who turned their talents to the fight against COVID-19. Image credit: Carlos Jones, ORNL
In early 2020, before the novel coronavirus had been named a pandemic, ORNL computational chemist Marti Head abruptly switched her focus — as did many scientists and researchers around the globe — to fight COVID-19.
The world was struggling to understand this new virus, known as severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2. But Head and others already knew that defeating such a highly transmissible pathogen was going to require a multipronged approach that included vaccines as well as multiple drug therapies.
Mainstream talk of therapeutics began to drop off after the FDA approved COVID-19 vaccines for emergency use authorization, and then later approved them for the prevention of COVID-19 disease in individuals 5 years of age and older.
Yet effective drug treatments still need to be in the mix, especially in anticipation of coronavirus variants expected over time.
“There’s been so much focus on vaccines that development of antibodies and antiviral drugs kind of gets overlooked,” Head said. “We absolutely, positively need vaccines … (to) help give us that kind of herd immunity to protect the widest population that we can. But we also need other tools.”
Development of drug treatments is complex, and it often takes years to move from scientific discovery to an approved, publicly available therapeutic. As the spread of COVID-19 ramped up in 2020, DOE launched the National Virtual Biotechnology Laboratory, or NVBL, with funding from the federal government’s CARES Act, and teams from across the agency’s national laboratory system began assembling.
One of those teams is Molecular Design for Medical Therapeutics. Led by Head, the group leverages expertise in artificial intelligence and computational screening techniques used for early-stage biomedical research.
Data gleaned from the team’s more recent efforts could help shorten the drug development timeline for COVID-19 drugs. The team also performs materials characterization at X-ray, light and neutron research facilities and conducts nanoscience research to accelerate scientific discovery for therapeutics targeting SARS-CoV-2.
As many national lab scientists turned from saving energy to saving lives, they gained a new level of expertise, resulting in the development of innovative research processes likely to have longer-term impacts as they shift back to their energy missions.
Energy mission, drug discovery
Head joined ORNL in February 2018 from GlaxoSmithKline to lead the lab’s Joint Institute for Biological Sciences, a collaboration with the University of Tennessee. She spent about two years developing strategies to fund biological research that would leverage the lab’s powerful user facilities and managing ORNL’s participation in the multinational lab consortium called Accelerating Therapeutics for Opportunities in Medicine, or ATOM.
When the nation sounded the alarm on COVID-19, she drew upon her decades of experience in computer-aided drug discovery to help DOE pull together a dream team of molecular biophysicists, computational biologists and chemists.
The NVBL molecular design team surveyed the larger biomedical research landscape. ORNL and several other national labs are using artificial intelligence and computational screening techniques — in combination with experimental validation — to identify and design drug therapies to target the SARS-CoV-2 virus. The team performed that research on ORNL’s Summit system, the nation’s most powerful supercomputer.
Promising approaches
Generally, SARS-CoV-2 spreads through airborne droplets from an infected person. Inside the body, the virus can quickly wreak havoc, invading healthy cells in myriad ways, making copies of itself and triggering a variety of biological responses ranging from the undetectable to the deadly. The United States has reported more than 800,000 COVID-19–related deaths, and millions have perished from this disease worldwide.
“As we’ve seen, the virus is mutating. That’s the nature of viruses, especially out in the real world in patients,” Head said. “(Viruses are) continually mutating, and the mutations that allow them to be more viable grow in importance in the world.”
“The rise of the delta variant brings to light the importance of a multipronged approach, including therapeutics, to tackle COVID-19,” she said. “Both in the bigger picture of having this arsenal to respond as the virus changes over time and also by recognizing that trying to kill something that’s not really alive … these are very hard tasks.”
Within months of launching their computational–experimental research, the molecular design team offered five promising drug therapy approaches, each focusing on a unique aspect of the virus’s life cycle.
One promising therapy targets the spike protein, one of the earliest and most studied points of attack against the novel coronavirus. The spikes that protrude from the virus’ outer layer form a corona, giving the virus its name. It invades the cell when the spike protein binds to the human ACE2 receptor. The molecular design team used computationally designed antibodies to prevent the spike protein from binding.
If the virus binds and then enters the cell, it can mature using two proteins — the main protease and the papain-like protease. One possible drug therapy would keep the virus from maturing by blocking this activity.
ORNL scientists contributed to this potential solution with computational data and experimentation. They also contributed to the design, synthesis and testing specific to the papain-like protease, a lesser studied but highly promising antiviral target. The team characterized the main protease through world-class crystallography and X-ray and neutron experiments by ORNL’s neutron scientists and performed inhibitor synthesis experiments at ORNL’s Center for Nanophase Materials Sciences.
After entering the cell, maturing and replicating, the virus begins to spread throughout the body. The team has researched small molecules with the potential to become drugs that inhibit viral spread. The results have been shared with experimentalists in controlled biocontainment labs to test the small molecules on live viruses.
An increase in viral load triggers the body’s immune response, while the virus itself negatively impacts the immune response by shutting it down. The team has also targeted ways to protect the body’s immune response by inhibiting the papain-like protease, a key protein associated with immune response. ORNL researchers designed new small molecules fine-tuned to keep the papain-like protease from allowing the novel coronavirus to replicate inside human cells.
In the final viral replication step, new spike proteins interact with viral RNA to make new virus copies. To inhibit this process, the team is investigating ways to prevent the new virus from escaping infected cells.
Each approach, according to Head, is designed to interrupt a specific interaction between the SARS-CoV-2 virus and human cells. To achieve maximum benefit in treating COVID-19, drug developers will likely pursue a combination therapy to attack the virus on multiple fronts and reduce viral load.
Of mice and medication
The journey from scientific discovery to an approved, marketable drug is long, and success is never guaranteed. But the NVBL molecular design team’s promising early results warrant the next step: a small mouse study.
ORNL researchers determined what they think are the best candidate drug molecules from a list of papain-like protease inhibitors that will be tested in mice infected with SARS-CoV-2. In collaboration with Stanford University and SLAC National Accelerator Laboratory, the team analyzed an X-ray crystal structure of their most promising compound and found that it does bind to the protein as expected. This structure will also help guide the development of improved compounds.
Vaccines became more widely available in spring 2021. However, the molecular design team’s story didn’t end. Head and her colleagues continue to share their research impact and results and seek out relationships in the medical research community.
“We have relationships with several medical schools and medical centers that could potentially follow up. And we have ongoing conversations and proposals in the works with the National Institutes of Health. There does have to be this passing of the baton for someone else to take it up and move it forward,” Head said.
See also: Interrupting COVID-19
